Ocular conditions characterized by elevated intraocular pressure, such as chronic open-angle glaucoma or secondary glaucoma, have been successfully treated by administration of methazolamide, and analogs, derivatives, and prodrugs thereof. Methazolamide is a carbonic anhydrase inhibitor that slows the formation of excess fluids behind the cornea by inhibiting a chemical reaction at the ciliary body.
Methazolamide is commercially available as an oral dose in 25 and 50 mg immediate release tablets, and is typically taken by a patient two to three times daily (50-150 mg/day). While effective, the high dosing frequency a patient must follow in order to attain effective therapy using the commercially available immediate release tablets reduces patient compliance because patients often miss doses as a result of patient forgetfulness or the inconvenience of having to take multiple doses throughout the day. Therefore, it is desirable to have an extended release methazolamide formulation that provides a longer period of pharmacological action after administration than is ordinarily obtained after administration of immediate-release dosage forms.
Many techniques have been used to provide controlled and extended-release pharmaceutical dosage forms in order to maintain therapeutic serum levels of medicaments. However, in the case of relatively water insoluble drugs such as methazolamide, developing a sustained release formulation generally requires considerable experimentation because it is often not possible to readily predict whether a particular extended release formulation will yield the desired sustained release profile while also maintaining suitable handling properties such as sufficient tablet hardness and appropriate friability.
Owing to the fact that water insoluble drugs tend to yield inconsistent drug release profiles, the task of preparing controlled release formulations of methazolamide has proven difficult. There is no commercially available extended release methazolamide formulation on the market.
U.S. Pat. No. 6,214,381 describes an extended-release methazolamide formulation that releases methazolamide over a period of 12 hours or less. However, this formulation is inadequate for once daily dosing because the methazolamide release profile is not optimal and does not provide sufficient coverage over a 24 hour period. Further, this formulation cannot be readily used in a 24 hour extended-release methazolamide formulation because attempts to extend the drug release profile from 12 hours to 24 hours using this formulation results in a composition which has inadequate handing properties (e.g. compressibility and friability issues), thereby precluding the composition's use as an orally administrable once-a-day dose.
Therefore, what are needed are extended release formulations of methazolamide that can deliver methazolamide over 24 hours with a suitable drug release profile when given to a subject, thus allowing once daily oral administration.